This invention describes a new type of X-ray contrast agents including their formulation and use. It has been found that iodinated alkenes could be used as X-ray contrast agents like the traditional iodinated aromatic contrast agents. The invention covers new iodinated alkenes, their use as X-ray contrast agents, as well as the use of known iodoalkenes as X-ray contrast agents.
Many of today""s X-ray contrast agents are based on triiodinated aromatics. The product iohexol (Omnipaque(copyright)) by Nycomed Imaging AS, given in FIG. 1, is an example of such a triiodinated aromatic.
There is a continuous need for new X-ray contrast agents, especially compounds with more simple structures than the traditional iodinated aromatic compounds. Such compounds can be prepared with fewer and easier synthetic steps than necessary for the preparation of triiodinated aromatic X-ray contrast agents.
It has previously been investigated whether certain iodinated alkenes may be used as X-ray contrast agents. H. Suter and H. Zutter describe in Pharm. Acta Helv. 50, 151-152, 1975, How fumaric acid derivatives were tested as potential X-ray contrast agents. Several fumaric acid derivatives were synthesised with different substituents that should give high aqueous solubility. One of those was diiodofumaric acid bis-[di-ethanol-amide]. The toxicity (LD 50 in mice, intravenous) was found to be less than 1 g/kg for all substances. The corresponding value for iohexol is 33.7 g/kg. The reason for this high toxicity is probably that the diiodofumaric acid structures are equivalent to a xe2x80x9cvinylogeous acid-iodidexe2x80x9d that can release iodide by an addition-elimination reaction with nucleophiles, see FIG. 2.
Fumaric acid derivatives and other iodoalkenes with electron withdrawing substituents will probably be unsuitable as X-ray contrast agents. The reason is that such compounds are able to release toxic iodide by an addition-elimination reaction with nucleophiles. In the development of new X-ray contrast agents it is generally desired that the contrast agent shall effect different biological mechanisms in the body as little as possible, because this generally results in lower toxicity and less negative clinical effects. Compounds that can release iodide in reactions with nucleophiles or electrophiles may cause toxic and negative biological effects and should not be used as contrast agents.
Iodoalkenes with electron-donor substituents may add electrophiles in the same way as enamines, see FIG. 3. This is undesirable too since the ammonium group can be cleaved hydrolytically. In addition the iodine is now bound to an sp3 hybridized on which is characteristic for alkylating agent again attack of nucleophiles will release iodide.
Partly as a result of the negative results from the investigation of fumaric acid derivatives it has been generally accepted that only iodinated aromatic compounds can be used as X-ray contrast agents. Other types of highly iodinated compounds that meet the property requirements for X-ray contrast agents like aqueous solubility, non-toxicity and stability have until now not been found.
It has now, surprisingly, been found that it is possible to use iodinated alkenes as X-ray contrast agents equivalent to iodinated aromatic contrast agents. Different from the compounds described by Suter and Zutter the iodinated alkenes in the present invention are characterized by that they neither contain electron withdrawing nor electron donating substituents at the Cxe2x95x90C double bond. As a consequence there are no problems caused by addition of electrophiles or nucleophiles followed by loss of iodide, while the utility as an X-ray contrasr agent is maintained.